The new integrase inhibitor dolutegravir (Tivicay) worked better than boosted darunavir for people starting HIV treatment for the first time, researchers reported at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2013) last week in Denver. Another study found that dolutegravir worked well across sex, race/ethnicity, and age groups.

Approval was based on favorable results from the phase 3 VIKING and SAILING trials in treatment-experienced patients and the SINGLE and SPRING studies in previously untreated people. SINGLE tested dolutegravir plus abacavir/lamivudine (the drugs in Epzicom) against Atripla (efavirenz/tenofovir/emtricitabine single tablet regimen), while SPRING-2 compared dolutegravir versus raltegravir (Isentress), the only other approved integrase inhibitor.

Dolutegravir vs Darunavir/Ritonavir

JudithFeinberg from the University of Cincinnati and colleagues presented findings from the FLAMINGO trial comparing dolutegravir against ritonavir-boosted darunavir (Prezista), a potent protease inhibitor, in people new to antiretroviral therapy (ART).

This multicenter, open-label, non-inferiority study enrolled 484 treatment-naive adults with HIV. Most participants (85%) were men, a majority were white, about 20% were black, and the median age was 34 years. At baseline the median CD4 T-cells count was 395 cells/mm3, with 10% having <200 cells/mm3. One quarter had high viral load (HIV RNA >100,000 copies/mL) at study entry.

Participants were randomly assigned to receive 50 mg once-daily dolutegravir or 800/100 mg once-daily darunavir/ritonavir. In addition they received investigator-selected NRTIs, with 75% using tenofovir/emtricitabine (the drugs in Truvada) and 25% using abacavir/lamivudine (Epzicom).

The researchers looked at the proportion of patients with undetectable viral load below 50 copies/ml at 48 weeks, along with safety, tolerability, health outcomes, and viral resistance. The randomized study will last through 96 weeks, followed by a non-randomized extension phase.

Results

By 48 weeks, 7% of patients taking dolutegravir discontinued treatment compared with 12% taking darunavir/ritonavir; the most common reasons for stopping in both arms were adverse events and loss to follow-up.

In a "snapshot" analysis, 90% of people taking dolutegravir and 83% taking darunavir/ritonavir achieved undetectable viral load, with dolutegravir meeting the criteria for statistical superiority.

Results were similar in a per-protocol or as-treated analysis, 91% and 84%, respectively.

Week 48 CD4 cell gains were the same in both arms at 210 cells/mm3.

The dolutegravir advantage was especially apparent among people with pre-treatment high viral load: 93% vs 70%, respectively.

Among people with low viral load, response was similar, at 88% and 87%, respectively.

Virological non-response was uncommon in both the dolutegravir and darunavir/ritonavir arms (6% and 7%, respectively).

Dolutegravir's superiority was attributable to fewer early withdrawals due to side-effects or other reasons.

Among people with virological failure, primary antiretroviral resistance mutations were rare in both arms (<1%).

Both regimens were general safe and well-tolerated, and most adverse events were mild to moderate.

Fewer people in the dolutegravir arm compared with the darunavir/ritonavir arm discontinued due to adverse events (1% vs 4%) and serious drug-related adverse events were uncommon (1 vs none, respectively).

However, people in the dolutegravir arm were had significantly smaller increases in LDL "bad" cholesterol (3.1 va 14.1mg/dl), and were less likely to have moderate or worse LDL elevation (2% vs 7%).

Small increases in serum creatinine -- a potential indicator of kidney toxicity -- were seen in the dolutegravir arm, which Feinberg explained was due to its inhibition of a renal transporter protein.

"Once-daily dolutegravir was superior to darunavir/ritonavir in treatment-naive HIV-1 infected patients," the researchers concluded. "Dolutegravir provides a potent and well-tolerated alternative to darunavir/ritonavir for this naive population."

Feinberg noted that while this open-label study was not double-blind and did not include placebo controls in order to reduce pill burden, these findings were "entirely consistent" with response rates seen in previous trials. She also noted that response rates did not differ based on which NRTIs were used.

Response in Subgroups

In a related report during the same session, Debbie Hagins from Chatham CARE Center in Savannah, Georgia, and colleagues looked at response rates among treatment-experienced participants in the SAILING and VIKING-3 trials according to sex, race/ethnicity, and age.

The SAILING study compared 50 mg once-daily dolutegravir vs 400 mg twice-daily raltegravir in participants who had never used integrase inhibitors. One-third of participants were women, 42% were black, and the media age was 43 years.

Results

In SAILING, overall response rates were 71% with dolutegravir vs 64% with raltegravir; CD4 cell gains were "robust" in both arms.

Virological efficacy was generally similar across sex, race, and age groups in both arms, though black patients and people over age 50 had somewhat lower response to both regimens:

o Women: 74% vs 60%

o Men: 70% vs 66%

o White: 75% vs 71%

o Black: 69% vs 58%

o Age <50: 73% vs 62%

o Age 50 or older: 65% vs 69%.

Tolerability was similar across subgroups, with low rates of adverse events leading to study withdrawal (5% or less in all study arms).

There were "nomeaningful differences" in adverse events leading to withdrawal by sex, race or age.

In the VIKING-3 study, which looked at patients with integrase inhibitor resistance, everyone received 50 mg twice-daily dolutegravir, first as "functional monotherapy" for 8 days, at which point the background regimen was optimized. Just under one-quarter were women, 27% were black, and the median age was 48 years.

Again, response rates were similar in the various subgroups, with a small disadvantage for black and older patients:

o Women: 71%

o Men: 68%

o White: 70%

o Black 65%

o Age <50: 73%

o Age 50 or older: 63%

Dolutegravir was well-tolerated overall, and adverse events leading to withdrawal did not exceed 4% in any subgroup.

Kidney Impairment

As described in a poster presentation, GlaxoSmithKline scientists evaluated safety and tolerability of dolutegravir for HIV patients with severe kidney dysfunction.

Dolutegravir is metabolized by the UGT1A1 and to a lesser extent CYP3A enzymes, the researchers noted as background. Dolutegravir is mostly secreted in bile and eliminated in feces, with about one-third being excreted in the urine.

In this small open-label study, participants with severe kidney impairment -- creatinine clearance <30 mL/min, but not on kidney dialysis -- received a single 50 mg dose of dolutegravir. They were matched with healthy volunteers of the same sex, age, and body mass index with normal kidney function (creatinine clearance >90 mL/min).

Overall, dolutegravir was well tolerated. Drug levels overlapped in the 2 groups, and the researchers concluded that the small observed differences in mean pharmacokinetic exposures were not likely to be clinically significant and did not require dose adjustment in people with impaired kidney function. They added that while no data are available for patients on kidney dialysis, this would not be expected to affect dolutegravir pharmacokinetic.

In an open-label study of 66 healthy HIV negative volunteers, drug levels were equivalent in participants receiving the 3-drug fixed-dose tablet and those taking dolutegravir and Epzicomseparately. The fixed-dose combination was well tolerated and was not affected by administration with a high-fat meal.

The researchers concluded that the fixed-dose coformulation was bioequivalent to the drugs administered separately and could be given "without regard to meals." If the co-formulation is found to be safe and effective in further clinical trials, it could offer a one-pill, once-daily single-tablet regimen that does not contain tenofovir, which can contribute to kidney and bone toxicity.